Cirrhosis is a chronic disease characterized by muscle wasting, decreased plasma concentrations of the branched-chain amino acids and presumed alterations in leucine and protein metabolism. The perceived need to correct these poorly understood abnormalities have provided the basis for ecently proposed but unproven nutritional programs in patients with chronic liver disease. The major objectives of these studies are to further investigate leucine metabolism in normal man and to define and quantify the alterations in protein degradation and protein synthesis in human subjects with cirrhosis. Using isotope tracers with mass spectrometric techniques, the effect of feeding, exercise and active hepatocellular inflammation upon the turnover of leucine and its keto-acid-keto- isocaproic acid will be examined. Based on the determinations of leucine and keto-isocaproic acid kinetics, estimates of whole body protein degradation and synthesis will be made. Furthermore, by measuring blood flow and arterial-venous gradients of leucine and KIC in the human forearm, protein turnover in the skeletal muscle compartment (based on the human forearm model) will be calculated and compared to whole body protein turnover. In addition, the rate and proportion of leucine degradation being used for energy versus lipid synthesis will be measured and compared to the turnover rates of leucine and keto-isocaproic acid. Finally, the importance of the route of nutrient administration (intestinal versus intravenous) in determining leucine metabolism will also be sought. It is anticipated that a precise understanding of leucine metabolism and its perturbations in vivo will provide rationale for recommending specific nutritional intervention and well focused pharmacologic therapy in this human disease.